This invention relates generally to methods and pharmaceutical compositions for the treatment of premature ejaculation. More particularly, the invention relates to the use of phosphodiesterase inhibitors in such methods and compositions.
Premature ejaculation is a debilitating yet common sexual dysfunction, and has been estimated to affect at least 30 to 40 percent of men at some point in their lives (Derogatis (1980) Med. Aspects Hum. Sexuality 14:1168-76; Frank et al. (1978) New Engl. J Med. 299:111-115; Schein et al. (1988) Fam. Pract. Res. J. 7(3):122-134). The condition can lead to an inability to enter into or sustain relationships, can cause psychological damage to sufferers, and can also impair reproductive success.
The Diagnostics and Statistical Manual of Mental Disorders (DSM-IV) (Washington, D.C.: American Psychiatric Association, 1994) delineates three criteria for a diagnosis of premature ejaculation: (1) xe2x80x9cpersistent or recurrent ejaculation with minimal sexual stimulation before, on or shortly after penetration and before the person wishes it,xe2x80x9d which is (2) associated with xe2x80x9cmarked distress or interpersonal difficulty,xe2x80x9d and (3) not due exclusively to the xe2x80x9cdirectxe2x80x9d effects of a xe2x80x9csubstancexe2x80x9d (with withdrawal from opioids cited as an example). The disorder is usually primary, but can also be secondary. xe2x80x9cPrimaryxe2x80x9d premature ejaculation refers to a lifelong, typically congenital condition, while xe2x80x9csecondaryxe2x80x9d premature ejaculation refers to a late onset condition, acquired after a period of normal functioning. Sexual dysfunctions such as premature ejaculation may also be further characterized as being generalized or limited to certain situations, and with respect to degree or frequency of the disturbance.
Premature ejaculation has historically been treated by psychosexual counseling in combination with xe2x80x9cbehavioralxe2x80x9d therapies such as the so-called xe2x80x9cpausexe2x80x9d and xe2x80x9cpause-squeezexe2x80x9d techniques. See St. Lawrence et al. (1992), xe2x80x9cEvaluation and Treatment of Premature Ejaculation: A Critical Review,xe2x80x9d Int. J. Psychiatry in Medicine 22(1):77-97; Semans, xe2x80x9cPremature Ejaculation: A New Approach,xe2x80x9d Southern Medical Journal 49:353-357, regarding the xe2x80x9cpausexe2x80x9d technique; and Masters and Johnson, Human Sexual Inadequacy, Little, Brown and Company, Boston, Mass., 1970, regarding the xe2x80x9cpause-squeezexe2x80x9d technique. Any improvement resulting from the aforementioned techniques is short-lived, however, and the cooperation of a man""s sexual partner is required. Typically, psychosexual counseling also requires the cooperation of the partner. Furthermore, many men may demand a quicker solution to the problem or are unwilling to attend counseling sessions. In addition, psychosexual counseling requires specialized therapists who may not be available to all patients, particularly in remote locations. Finally, counseling benefits only a subset of patients, i.e., those for whom the condition is psychogenic. Psychological therapies cannot alleviate premature ejaculation resulting from non-psychological causes.
Topical anesthetic agents and intracavernosal injection of medicaments have also been employed to treat patients suffering from premature ejaculation. However, anesthetic agents are problematic insofar as they necessarily decrease tissue sensitivity and thereby diminish sexual pleasure. Also, topical anesthetics can be transferred to sexual partners and thereby decrease their sensitivity and pleasure as well. Intracavemosal injection is associated with pain and discomfort, and is not a preferred mode of drug administration. Various devices have also been proposed to delay ejaculation; however, such devices can be awkward, inconvenient and embarrassing to use.
Methods for treating premature ejaculation by systemic administration of several different antidepressant compounds have been described (U.S. Pat. Nos. 4,507,323, 4,940,731, 5,151,448, and 5,276,042; PCT Publication No. WO95/13072). However, these drugs may not be effective for all patients, and the side effects of these drugs can halt treatment or impair patient compliance. Disease states or adverse interactions with other drugs may contraindicate the use of these compounds or require lower dosages that may not be effective to delay the onset of ejaculation.
For example, administration of the antidepressant fluoxetine has been claimed to treat premature ejaculation; see U.S. Pat. No. 5,151,448. However, the administration of fluoxetine has many undesired aspects. Patients with hepatic or renal impairments may not be able to use fluoxetine due to its metabolism in the liver and excretion via the kidney. Systemic events during fluoxetine treatment involving the lungs, kidneys or liver have occurred, and death has occurred from overdoses. In addition, numerous side effects are associated with oral fluoxetine administration include hair loss, nausea, vomiting, dyspepsia, diarrhea, anorexia, anxiety, nervousness, insomnia, drowsiness, fatigue, headache, tremor, dizziness, convulsions, sweating, pruritis, and skin rashes. Fluoxetine interacts with a range of drugs, often by impairing their metabolism by the liver.
U.S. Pat. No. 4,940,731 describes the oral or parenteral administration of sertraline for treating premature ejaculation. It has been recognized that sertraline shares many of the same problems as fluoxetine; see Martindale, The Extra Pharmacopoeia, 31st edition, at p. 333 (London: The Royal Pharmaceutical Society, 1996). Sertraline is metabolized in the liver, and is excreted in the urine and feces. Thus, patients with cirrhosis must take lower doses, and caution must be exercised when administering sertraline to patients with renal impairment. Individuals taking monoamine oxidase inhibitors cannot take sertraline due to the risk of toxicity. Side effects resulting from oral sertraline administration include nausea, diarrhea, dyspepsia, insomnia, somnolence, sweating, dry mouth, tremor and mania. Rare instances of coma, convulsions, fecal incontinence and gynecomastia have occurred in patients undergoing sertraline therapy.
U.S. Pat. No. 5,276,042 describes the administration of paroxetine for the treatment of premature ejaculation. Paroxetine is predominantly excreted in the urine, and decreased doses are recommended in patients with hepatic and renal impairments. Like sertraline, paroxetine cannot be given to patients undergoing treatment with a monoamine oxidase inhibitor. Side effects from oral administration of paroxetine include hyponatremia, asthenia, sweating, nausea, decreased appetite, oropharynx disorder, somnolence, dizziness, insomnia, tremor, anxiety, impaired micturition, weakness and paresthesia
All of the known methods to treat premature ejaculation are thus problematic in one or more respects. An ideal method would not require ongoing (xe2x80x9cchronicxe2x80x9d) drug therapy or use of active agents with numerous and/or serious side effects. An ideal method would be useful in the treatment of individuals with secondary, acquired premature ejaculation as well as those suffering from a primary, lifelong condition. The method would not involve application of anesthetic agents, intracavemosal drug administration, or use of devices, and would not require ongoing counseling sessions.
It has now been discovered by the present inventors that phosphodiesterase (PDE) inhibitors, as a class, are unexpectedly useful in treating premature ejaculation, and meet all of the aforementioned requirements. The discovery is indeed surprising insofar as PDE inhibitorsxe2x80x94of which sildenafil citrate, commercially available as Viagra(copyright), is a representative compoundxe2x80x94are used to treat impotence and thus enhance sexual function, i.e., as opposed to modulating sexual function in a manner that allows delay of ejaculation.
Phosphodiesterases are a class of intracellular enzymes involved in the metabolism of the second messenger nucleotides, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP) (see, e.g., Doherty, xe2x80x9cOral, Transdermal and Transurethral Therapies for Erectile Dysfunctionxe2x80x9d in Male Infertility and Dysfunction, Hellstrom, ed., Chapter 34 (New York, N.Y.: Springer-Verlag, 1997)). Numerous phosphodiesterase inhibitors have previously been described in the literature for a variety of therapeutic uses, including treatment of obstructive lung disease, allergies, hypertension, angina, congestive heart failure and depression (see, e.g., Goodman and Gilman""s The Pharmacological Basis of Therapeutic Ninth Edition, Chapter 34). Oral and parenteral administration of phosphodiesterase inhibitors, as alluded to above, has also been suggested for the treatment of erectile dysfunction (Doherty, supra; see also PCT Publication Nos. WO 96/16644 and WO 94/28902).
As explained by Komas et al. in Phosphodiesterase Inhibitors, Schudt et al., Eds., Ch. 6 (San Diego, Calif.: Academic Press, 1996), those initially working in the field partially purified what was believed to be a single enzyme responsible for specifically hydrolyzing the 3xe2x80x2-bond of cyclic nucleotides. However, it later became clear that multiple forms of phosphodiesterase inhibitors were present in different tissues; the enzymes were classified into three major groups, one of which exhibited high affinity for cAMP and designated as the xe2x80x9clow Kmxe2x80x9d cAMP PDE. This xe2x80x9clow Kmxe2x80x9d cAMP PDE was ultimately discovered to consist of two distinct isoenzymes having entirely different properties, including physical properties, kinetic characteristics and inhibitor specificities. One isoenzyme was found to be very sensitive to inhibition by cilostamide and cGMP, and is now known as the cAMP-specific, cGMP-inhibited cyclic nucleotide phosphodiesterase (cGI-PDE) or PDE III, while the second isoenzyme was classified as PDE IV. Komas et al., supra.
The phosphodiesterases have now been classified into ten major families, Types I-XI, based on amino acid or DNA sequences. The members of the family vary in their tissue, cellular and subcellular distribution, as well as their links to cAMP and cGMP pathways. For example, the corpora cavernosa contains: Type III phosphodiesterases, which as explained above are cAMP-specific cGMP inhibitable; Type IV phosphodiesterases, the high affinity, high-specificity cAMP-specific form; and Type V phosphodiesterases, one of the cGMP-specific forms.
Accordingly, the present invention is addressed to the limitations of the prior art, and provides a novel treatment for individuals suffering from either primary or secondary premature ejaculation, wherein drug administration may be on an xe2x80x9cas-neededxe2x80x9d basis rather than necessarily involving chronic pharmacotherapy, and does not involve use of anesthetic agents, intracavemosal drug administration, or use of devices. To the best of applicants"" knowledge, the present method of treating premature ejaculation is novel and completely unsuggested by the prior art.
It is a primary object of the invention to address the above-described need in the art by providing a novel method for the treatment of premature ejaculation by administering an effective amount of a phosphodiesterase inhibitor to an individual in need of such therapy, wherein the term xe2x80x9cphosphodiesterase inhibitorxe2x80x9d includes phosphodiesterase inhibitors per se as well as pharmaceutically acceptable (and pharmacologically active) salts, esters, amides, prodrugs, active metabolites and other derivatives thereof.
It is another object of the invention to provide such a method wherein the phosphodiesterase inhibitor is administered orally.
It is another object of the invention to provide such a method wherein the phosphodiesterase inhibitor is administered transmucosally, e.g., via the sublingual, buccal, nasal, transurethral or rectal routes, or via inhalation.
It is another object of the invention to provide such a method wherein the phosphodiesterase inhibitor is administered topically, transdermally, parenterally, or by other routes.
It is still another object of the invention to provide such a method wherein the phosphodiesterase inhibitor is a Type III inhibitor, a Type IV inhibitor, a Type V inhibitor, or a nonspecific phosphodiesterase inhibitor.
It is yet another object of the invention to provide such a method wherein the phosphodiesterase inhibitor is a Type V inhibitor.
It is a further object of the invention to provide such a method wherein drug administration is on an as-needed basis.
It is still a further object of the invention to provide such a method wherein the active agent is administered in a controlled release formulation.
It is yet a further object of the invention to provide such a method wherein the controlled release formulation is a sustained release formulation and/or a delayed release formulation.
It is an additional object of the invention to provide such a method wherein the controlled release formulation is a sustained release formulation that provides drug release over a time period in the range of about 4 to about 48 hours.
It is still an additional object of the invention to provide a composition containing an amount of a phosphodiesterase inhibitor effective for the treatment of premature ejaculation.
It is another object of the invention to provide a packaged kit comprised of a container housing a phosphodiesterase inhibitor formulation as provided herein and instructions for administering the formulation in a manner effective to treat premature ejaculation.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In a first aspect of the invention, a method is provided for the treatment of an individual prone to or suffering from premature ejaculation, the method comprising administering to an individual in need of such treatment a pharmaceutical formulation containing a therapeutically effective amount of an active agent selected from the group consisting of phosphodiesterase inhibitors and pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, active metabolites, and other derivatives thereof. Administration of the pharmaceutical formulation may be on an xe2x80x9cas-neededxe2x80x9d basis or within the context of an ongoing dosage regimen. By xe2x80x9cas-neededxe2x80x9d dosing, also known as pro re nata dosing, is meant the administration of a single dose of the active agent at some time prior to anticipated sexual activity. Administration can be immediately prior to sexual activity, or up to about 2 or 3 hours prior to anticipated sexual activity, although with sustained release dosage forms, a single dose can provide therapeutic efficacy over an extended time period in the range of about 4 to 48 hours, depending on the formulation. Drug delivery may be accomplished through any mode of administration, including, but not limited to, the oral and transmucosal routes.
In a further aspect of the invention, pharmaceutical formulations are provided for carrying out the method of the invention. The pharmaceutical formulations comprise a therapeutically effective amount of an active agent as provided herein, a pharmacologically acceptable carrier or vehicle, generally a carrier or vehicle suitable for transmucosal drug administration, and, optionally, an enhancer. Other types of components may be incorporated into the formulation as well, e.g., excipients, surfactants, preservatives (e.g., antioxidants), stabilizers, chelating agents, and the like, as will be appreciated by those skilled in the art of pharmaceutical formulation preparation and drug delivery.
In another aspect of the invention, a packaged kit is provided for a patient to use in the treatment of premature ejaculation. The kit includes a pharmaceutical formulation of a phosphodiesterase inhibitor, a container housing the pharmaceutical formulation during storage and prior to administration, and instructions, e.g., written instructions on a package insert or label, for carrying out drug administration in a manner effective to treat premature ejaculation. The pharmaceutical formulation may be any formulation described herein, e.g., an oral dosage form containing a unit dosage of the phosphodiesterase inhibitor, the unit dosage being a therapeutically effective dosage for treatment of premature ejaculation.